Pain is initiated when the peripheral terminals of a subgroup of sensory neurons are activated by noxious chemical, mechanical or thermal stimuli. These neurons, called nociceptors, transmit information regarding tissue damage to pain-processing centres in the spinal chord and brain (Fields, H. L. Pain, McGraw-Hill, New York, 1987). Nociceptors are characterized in part, by their sensitivity to capsaicin, a vanilloid-containing compound, and a natural product of capsicum peppers that is the active ingredient of many “hot” and spicy foods. In mammals, exposure of nociceptor terminals to capsaicin leads initially to excitation of the neuron and the consequent perception of pain and local release of inflammatory mediators. With prolonged exposure, nociceptor terminals become insensitive to capsaicin, as well as to other noxious stimuli (Szolcsanyi, J. in Capsaicin in the Study of Pain (ed. Wood, J.) 1-26 (Academic, London, 1993). This latter phenomenon of nociceptor desensitization underlies the seemingly paradoxical use of capsaicin as an analgesic agent in the treatment of painful disorders ranging from viral and diabetic neuropathies to rheumatoid arthritis (Campbell, E. in Capsaicin and the Study of Pain (ed. Wood, J.) 255-272 (Academic, London, 1993); Szallasi, A. et al. (1996) Pain 68, 195-208). Some of this decreased sensitivity to noxious stimuli may result from reversible changes in the nociceptor, but the long-term loss of responsiveness can be explained by death of the nociceptor or destruction of its peripheral terminals following exposure to capsaicin (Jancso, G. et al. (1977) Nature 270, 741-743).
The cellular specificity of capsaicin action and its ability to evoke the sensation of burning pain have led to speculation that the target of capsaicin action plays an important physiological role in the detection of painful stimuli. Indeed, capsaicin may elicit the perception of pain by mimicking the actions of a physiological stimulus or an endogenous ligand produced during tissue injury (James, I. F., Kinkina, N. N. & Wood, J. N. in Capsaicin in the Study of Pain (ed. Wood, J. N.) 83-104 (Academic, London, 1993).
Caterina M. J. et al. have recently determined the molecular basis underlying this phenomenon by characterizing a functional cDNA that encodes a vanilloid receptor (VR-1) in rat sensory ganglia (Caterina M. J. et al., (1997) Nature 389:816-824). VR-1 is a vanilloid-gated, nonselective cation channel that resembles members of the transient receptor potential (TRP) channel family, first identified as components of the Drosophila phototransduction pathway (Montell et al. (1989) Neuron 2:1313-1323).
Table of ContentsA.Summary of the Invention -2-B.Brief Description of the Drawings -6-C.Detailed Description of the Invention -8-I.Isolated Nucleic Acid Molecules-12-II.Isolated hVR-1, hVR-2, and rVR-2 Proteins and-22-Anti-hVR-1, Anti-hVR-2, and Anti-rVR-2AntibodiesIII.Recombinant Expression Vectors and Host Cells-31-IV.Pharmaceutical Compositions-39-V.Uses and Methods of the Invention-43-A.Screening Assays-44-B.Detection Assays-49-1.Chromosome Mapping-50-2.Tissue Typing-51-3.Use of Partial hVR-1, hVR-2, and-52-rVR-2 Sequences in Forensic BiologyC.Predictive Medicine-53-1.Diagnostic Assays-53-2.Prognostic Assays-55-3.Monitoring of Effects During Clinical-60-TrialsD.Methods of Treatment-61-1.Prophylactic Methods-61-2.Therapeutic Methods-62-3.Pharmacogenomics-63-D.Examples-65-